Under the conditions of natural environment body rhythms are adapted to the regular alternation of day and night, and the much slower monthly and seasonal cycles. The human seasonality is perceptive and indeed very important in some circumstances (Seasonal Affective Disorder, or Winter Depression) despite the almost universal use of artificial lighting and heating. Nevertheless, humans remain a diurnal species and often, the social organization leads to specific conflicts between the physiology and the environment.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized exclusively in the vertebrate pineal gland in rhythmic manner with elevated pineal, cerebrospinal fluid and peripheral blood levels at night. It has a very well expressed, high-amplitude circadian rhythm, controlled by the circadian biological clock. The phase of the rhythm is synchronized by light to the prevailing photoperiod and thus, melatonin serves as a fundamental biochemical transducer of the photoperiodic information from the environment. The most-well documented action of melatonin is its ability to drive the reproductive competence in a number of seasonal breeders, presumably acting on the endogenous biological clock. Recent research, however, pointed out at diverse sites and modes of action of melatonin, related to a synchronization necessary for the expression of other endogenous rhythms within the circadian organization. Therefore, one should expect that melatonin is involved in a number of pathological conditions, related to circadian disorganization and disease (chronopathology).
In recent years the discovery and the description of high affinity melatonin receptors in the Central Nervous System of vertebrates led to a rapid development in the field. The sites and cellular mechanism(s) of action of the indole were described, some melatonin analogues were synthesized and models for testing their activity described.
Among the possible applications of melatonin and its potent agonists in human medicine should be mentioned:
1. Circadian disorientation and disease (chronopathology). PA1 1.a. Jet- lag. Strong circadian desynchronization is observed in air travellers rapidly crossing more than five time zones, the phenomenon being more prominent when crossing Eastward. Jet-lag has been treated with melatonin, given orally with appropriate schedule [Arendt et al. Ergonomics 30, 1379-1391 (1987); U.S. Pat. Nos. 4,600,723 and 5,242,941)], but there are serious problems related to the individual absorption rates and melatonin bioavailability [Waldhauser et al., Neuroendocrinology 39, 307-313 (1984)]. PA1 1.b. Sleep disturbances, due to circadian alesynchronization, e.g. delayed sleep phase syndrome. Timed melatonin treatment produces notable phase-advances in subjects affected by delayed sleep phase syndrome, and leads to a stable improvement of the timing of sleep [Dahlitz et al., Lancet i337, 11121-1124 (1991)]. PA1 1.b.1. Disorders in the temporal, macrostrutural and microstructural organization of the sleep. Melatonin will also probably become an important supplement therapy when benzodiazepines (BDZ) are employed for the treatment of insomnia. The BDZ have notable dose-dependent side effects, provoking paradoxical repercussion on sleep, diurnal anxiety and suicidal ideations, followed by development of tolerance to the BDZ therapy. Melatonin administration in combination with low BZD doses (about two times lower than prescribed) has been able to significantly improve the sleep temporal pattern, influencing the sleep macrostructure, and mainly the microstructure, while leaving intact the sleep architecture. This allows for a substantial decrease in the BZD doses, when used to treat sleep disturbances, thus avoiding the undesirable BZD doserelated side effects. PA1 1.c. Shift work. People working on shifts very often disrupt their circadian organization with the consequences of disturbances in sleep-activity cycles, insomnia, diurnal hypoactivity, depression. Melatonin endogenous rhythm frequently is disorganized. PA1 1.d. Treatment of desynchronized blind people. Patients that are unable to perceive light usually suffer of disturbances related to their state of free-running circadian rhythmicity. In most of the cases synchronization of their temporal activity patterns has been achieved by timed oral melatonin treatment [Palm et at., Ann. Neurol. 29, 336-339 (1991)]. PA1 2. Aging. With the advancement in age the amplitudes of both pineal and serum melatonin decline. Therefore, a number of problems, related to old age have been attributed to pineal dysfunction, but most probably we should consider it circadian dysregulation, partially related also to altered sensitivity to light. PA1 2.a Correction of the alterations in the circadian rhythms (see above). PA1 2.b. Sleep disturbances (see above). PA1 2.c. Immune deficit.
The major applications are:
The major applications are:
The immunomodulatory properties of melatonin have been repeatedly demonstrated in the recent years, using different in vivo and in vitro models. The action of melatonin is dependent on the time of administration; therefore, one more time direct influence on the circadian organization involving oscillation patterns is evident, this time in terms of immune competence.
Melatonin, given orally in doses of 0.25-10 mg has been used successfully to treat circadian disorders due to jet-lag [Arendt et al., Ergonomics 30, 1379-1393 (1987); U.S. Pat. Nos. 4,600,723 and 5,242,941)]. Moreover, timed oral melatonin treatment apparently shifts the human circadian clock according to a phase-response curve (U.S. Pat. 5,242,941).
However, oral administration of melatonin raises the following problems: 1. High, non-physiological peripheral blood melatonin levels are achieved with dosages of 1-10 mg melatonin given orally. 2. Peripheral blood melatonin levels of abnormally short duration are achieved with 0.25-0.5 mg melatonin given orally.
In both cases there is a serious drawback: either the concentration levels achieved are too high (30-1000 times higher than the endogenous ones, when 1-10 mg melatonin is given orally), or the duration of the melatonin bioavailability in the peripheral blood is abnormally short: (one-three hours with 0.25-0.5-1 mg melatonin given orally). This is due to the very short half-life of melatonin in the blood: elimination half-life (T1/2)=27-30 minutes in humans. The natural, endogenous melatonin bioavailability is about six-eight hours: a direct result of a continuous synthesis and release of melatonin from the pineal gland. The duration of the melatonin signal is crucial for its sustained biological effect.
In order to obtain plasmatic levels of comparable to the endogenous melatonin peak duration, oral or parenteral application of exogenous melatonin must be in very high doses (80-100 mg/dose). A similar treatment results in excessive melatonin concentrations during the first hours (60-240 minutes after administration), followed by a rapid decrease.
Moreover, when treating circadian rhythm disorders by oral melatonin, the compound is administered during daytime; thus, high pharmacological levels of melatonin are achieved with the higher dose range at inappropriate time of the photocycle (endogenous melatonin levels are high at night).
Another problem is connected with the differences in the absorption from individual to individual. The hematic levels after oral administration of melatonin may vary from individual to individual even more that 100 times, with the same dose employed.
There is also a great need for compounds that behave as selective melatonin agonists for the different type of melatonin receptor in the hypothalamic suprachiasmatic nuclei (SCN), which is the site of the circadian biological clock. The mammalian SCN express a different melatonin receptor subtype (isoform).